Substituted pyrimidines as inhibitors for a Rho family of GTP-ases

ABSTRACT

The present invention relates to compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof: 
     
       
         
         
             
             
         
       
     
     It further discloses a pharmaceutical composition comprising the compounds of Formula (I) and their uses, in particular in the treatment of diseases or disorders associated to increased relative to physiological or desired RhoJ/Cdc42 levels of expression or function.

STATEMENT OF FEDERAL SUPPORT

This invention was made with government support under Grant No.5R01CA151513-05 awarded by the Department of Health and Human Services(DHHS). The government has certain rights in the invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a U.S. national stage of PCT Application No.PCT/IB2018/053047, entitled “TRISUBSTITUTED PYRIMIDINE COMPOUNDS ANDCOMPOSITIONS FOR THE TREATMENT OF CANCER, RETINAL DISORDERS, ANDCARDIOMYOPATHIES” to De Vivo et al., filed May 2, 2018, whichapplication claims priority to Italian Patent Application No.102017000047189 filed May 2, 2017, the disclosures of which areincorporated herein by reference in their entireties.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not Applicable

THE NAMES OF PARTIES TO A JOINT RESEARCH AGREEMENT

Not Applicable

INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A COMPACT DISC

Not Applicable

FIELD OF THE INVENTION

The present invention relates to novel RhoJ inhibitors for the treatmentof cardiomyopathies, retinal disorders and cancers, in particularmelanoma.

BACKGROUND OF THE INVENTION

The incidence of melanoma, a type of cancer that develops from themalignant transformation of melanocytes, is increasing while,unfortunately, traditional therapies such as dacarbazine and high-doseof interleukin-2 (IL-2) chemotherapies are cytotoxic and have poorefficacy, which reinforce the need for new therapeutic approaches.

More recent strategies include the use of BRAF inhibitors, such asvemurafenib. Also, immunotherapeutic approaches using antibodiesblocking immune checkpoint molecules, such as ipilimumab, that targetsthe anti-cytotoxic T lymphocyte antigen 4 (CTLA-4), are currently usedto treat unresectable melanoma. Additional studies use a combination ofPD1 inhibitors, such as nivolumab, with ipilimumab. While thesetherapies can cause dramatic response in some patients, only 30% ofpatients respond to these therapies. Improved therapies are particularlyneeded for early stage disease, where only interleukin 2 and oncolyticviral therapies have been used with very limited success.

In this context, an alternative and promising approach is thecombination of therapies where multiple agents and traditionalanticancer modalities (radiation, chemotherapy or surgery) are usedtogether to enhance treatment efficacy and reduce side effects.

All these possible therapeutic strategies, however, have not resulted ina significant decline in the mortality of melanoma patients andprogression of metastatic melanoma. Intrinsic and/or acquired resistanceto chemotherapies remains a major issue and generates a strong need toidentify new pathways to treat it. In addition, identifying agents thathave limited toxicity and could be used to treat early stage disease(stage III) would have significant therapeutic applicability.

RhoJ is currently presented as a validated target in the combinedtreatments strategy since its expression modulates the development ofmelanoma. RhoJ is a member of the Rho-family of small GTPases, known tobind and activate PAK kinases. Functional validation studies revealedthat RhoJ activates PAK1, which then inhibits p53 signaling andapoptosis pathways in melanoma cells in vitro.

Additional studies showed that RhoJ and PAK1 also modulate melanoma cellmigration and invasion in vitro, as well as tumor growth and invasion inmelanoma xenograft model. While RhoJ was known to have a role inendothelial cell biology and angiogenesis, it was not known whether RhoJhad cell autonomous effects on the growth of melanocytic tumors. Recentstudies have determined that RhoJ modulates the growth and developmentof melanoma tumors in autochthonous mouse models and is expressed at ahigher level in stage III as compared to stage IV melanomas. Overall,these in vitro and in vivo studies revealed that RhoJ and PAK1accelerate the growth of nascent melanoma tumors, inhibit apoptosis, andstimulate angiogenesis. Recent studies indicated that RhoJ operates intumor cells to inhibit apoptosis by blocking the phosphorylation of BAD,which prevents BAD from inducing apoptosis. RhoJ interaction inhibitorsblocked PAK kinase induced BAD phosphorylation, a similar effect to whatwas observed with PAK inhibitors.

Furthermore, RhoJ is also considered to play a central role in thepathophysiology of cardiomyopathies, such as Dilated CardioMyopathies(DCM) and a possible therapeutic target to specifically manipulateendothelial filopodia projections.

For these reasons blocking RhoJ can be considered a useful tool to treatpathologies such as cardiomyopathies, retinal disorders, stage III orstage IV melanomas, and other cancers which show resistance to othertherapies.

Accordingly, there is a need for novel compounds to inhibit RhoJ.

BRIEF SUMMARY OF THE INVENTION

The aim of the present invention is to provide novel compounds acting asRhoJ inhibitors.

The aforementioned objective has been met according to compounds ofclaim 1, to a pharmaceutical composition of claim 7, to the uses ofclaims 10, 11 and 12. Preferred embodiments are set out within thedependent claims.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

The present invention will now be described in detail with reference tothe annexed drawings, wherein:

FIG. 1 illustrates apoptosis induced in WM3248 melanoma cells by RhoJinteraction inhibitor ARN12405 (compound 1) measured by flow cytometryusing AnnexinV and PI;

FIG. 2 illustrates block of RhoJ PAK interaction in cell lysates fromWM3248 cells incubated with compound 1 (ARN12405) evaluated by SDS PAGEand immunoblotting with a (panel A) RhoJ antibody; (panel B) cdc42antibody; (panel C) Rac1 antibody. (panel D) Cells treated with compound1 (ARN12405) at a concentration of 10 μm or 50 μm.

DETAILED DESCRIPTION OF THE INVENTION

The following paragraphs provide definitions of the various chemicalmoieties of the compounds according to the invention and are intended toapply uniformly throughout the specification and claims unless anotherwise expressly set out definition provides a broader definition.

The term “alkyl”, as used herein by itself or as a part of anothersubstituent, refers to aliphatic hydrocarbon groups. Such term includeslinear (unbranched) chains or branched chains, which may be fullysaturated, mono- or polyunsaturated.

The term “unsaturated” aliphatic hydrocarbon group encompasses alkenyland alkynyl.

The term “alkenyl”, as used herein, refers to alkyl groups, preferablyhaving from 2 to 6 carbon atoms and containing at least onecarbon-carbon double bond.

The term “alkynyl”, as used herein, refers to alkyl groups, preferablyhaving from 2 to 6 carbon atoms and containing at least onecarbon-carbon triple bond.

Non-limiting examples of alkyl groups according to the invention are,for example, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl,tert-butyl, n-pentyl, iso-pentyl, n-hexyl, ethenyl, 1-propenyl,2-propenyl, 1- or 2-butenyl, ethynyl, 1-propynyl, 2-propynyl, 1- or2-butynyl and the like.

The term “alkoxy”, as used herein, refers to an alkyl group that islinked to the remainder of the compound by an oxygen atom.

The term “halogen”, as used herein, refers to fluorine, chlorine,bromine and iodine.

The term “aromatic ring”, as used herein, refers to a moiety wherein theconstituent carbon atoms make up an unsaturated ring system, all atomsin the ring system are sp² hybridized and the total number ofn-electrons is equal to 4n+2, wherein n is an integer.

The term “heteroaromatic ring”, as used herein, refers to an aromaticring as defined above wherein one to four carbon atoms are independentlyreplaced by heteroatoms chosen from the group consisting of nitrogen,oxygen and sulphur. Non-limiting examples of heteroaromatic ring groupsare, for example, pyrrolyl, furyl, thiophenyl, imidazolyl, pyrazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, indolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, benzopyrazolyl, benzoxazolyl,benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, triazolyl,oxadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl.

Unless otherwise indicated, the term “substituted”, as used herein,means that one or more hydrogen atoms of the above mentioned groups arereplaced with another non-hydrogen atom or functional group, providedthat normal valencies are maintained and that the substitution resultsin a stable compound.

The term “pharmaceutically acceptable salts” refers to salts of thebelow identified compounds of Formula (I) that retain the desiredbiological activity and are accepted by regulatory authorities.

As used herein, the term “salt” refers to any salt of a compoundaccording to the present invention prepared from an inorganic or organicacid or base and internally formed salts. Typically, such salts have aphysiologically acceptable anion or cation.

Furthermore, the compounds of Formula (I) may form an acid addition saltor a salt with a base, depending on the kind of the substituents, andthese salts are included in the present invention, as long as they arepharmaceutically acceptable salts.

Examples of such salts include, but are not restricted to acid additionsalts formed with inorganic acids (e.g. hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, nitric acid, and the like), andsalts formed with organic acids such as acetic acid, trifluoroaceticacid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaricacid, maleic acid, ascorbic acid, benzoic acid, alginic acid,polyglutamic acid and naphthalene sulfonic acid.

Physiologically or pharmaceutically acceptable salts are particularlysuitable for medical applications because of their greater aqueoussolubility relative to the parent compound.

Pharmaceutically acceptable salts may also be prepared from other saltsincluding other pharmaceutically acceptable salts of the compounds ofFormula (I) using conventional methods.

Those skilled in the art of organic chemistry will appreciate that manyorganic compounds can form complexes with solvents in which they arereacted or from which they are precipitated or crystallized. Thesecomplexes are known as “solvates”. For example, a complex with water isknown as a “hydrate”. Solvates of the compounds of the invention arewithin the scope of the invention. The compounds of Formula (I) mayreadily be isolated in association with solvent molecules bycrystallization or evaporation of an appropriate solvent to give thecorresponding solvates.

The compounds of Formula (I) may be in crystalline form. In certainembodiments, the crystalline forms of the compounds of Formula (I) arepolymorphs.

The subject invention also includes isotopically-labelled compounds,which are identical to those recited in Formula (I) and following, butdiffer for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that can beincorporated into the compounds of the invention and pharmaceuticallyacceptable salts thereof include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, sulfur, fluorine, iodine, and chlorine, such as ²H,³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, ¹²⁵I.

Compounds of the present invention and pharmaceutically acceptable saltsof said compounds that contain the aforementioned isotopes and/or otherisotopes of other atoms are within the scope of the present invention.Isotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H, ¹⁴C are incorporated,are useful in drug and/or substrate tissue distribution assays.Tritiated, i.e. ³H, and carbon-14, i.e. ¹⁴C, isotopes are particularlypreferred for their ease of preparation and detectability. ¹¹C and ¹⁸Fisotopes are particularly useful in PET (Positron Emission Tomography),and ¹²⁵I isotopes are particularly useful in SPECT (Single PhotonEmission Computerized Tomography), all useful in brain imaging.Furthermore, substitution with heavier isotopes such as deuterium, i.e.2H, can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically-labelled compounds of Formula (I) and following of thisinvention can generally be prepared by carrying out the proceduresdisclosed in the Schemes and/or in the Examples below, by replacing anon-isotopically-labelled reagent with a readily availableisotopically-labelled reagent.

Certain groups/substituents included in the present invention may bepresent as isomers or in one or more tautomeric forms. Accordingly, incertain embodiments, the compounds of Formula (I) may exist in the formof other tautomers or geometrical isomers in some cases, depending onthe kinds of the substituents. In the present specification, thecompounds may be described in only one form of such isomers, but thepresent invention includes all such isomers, isolated forms of theisomers, or a mixture thereof. Furthermore, the compounds of Formula (I)may have asymmetric carbon atoms or axial asymmetries in some cases and,correspondingly, they may exist in the form of optical isomers such asan (R)-form, an (S)-form, and the like. The present invention includeswithin the scope all such isomers, including racemates, enantiomers andmixtures thereof.

In particular, within the scope of the present invention are includedall stereoisomeric forms, including enantiomers, diastereoisomers, andmixtures thereof, including racemates and the general reference to thecompounds of Formula (I) includes all the stereoisomeric forms, unlessotherwise indicated.

In general, the compounds or salts of the invention should beinterpreted as excluding those compounds (if any) which are sochemically unstable, either per se or in water, that they are clearlyunsuitable for pharmaceutical use through all administration routes,whether oral, parenteral, or otherwise. Such compounds are known to theskilled chemist.

According to a first aspect of the invention, compounds of Formula (I):

or pharmaceutically acceptable salts or solvates thereof are provided.

In the compounds of Formula (I):

X₁ and X₂ are independently selected from the group consisting of CH₂,NR₂ and O provided that X₁ and X₂ are not both NR₂, both 0 or NR₂ and Oat the same time;

Y is selected from the group consisting of CH and N;

A and A′ are independently selected from the group consisting of a6-membered heteroaromatic ring that contains 1 or 2 nitrogen atoms and a6-membered aromatic ring optionally substituted at any position with asubstituent selected from the group consisting of C₁₋₆alkyl, halogen,halo-C₁₋₆alkyl, hydroxyl, alkoxy-C₁₋₆alkyl, amino, amino-C₁₋₆alkyl andamino-diC₁₋₆alkyl;

R₁ is selected from the group consisting of hydrogen and C₁₋₆alkyl;

R₂ is selected from the group consisting of hydrogen, C₁₋₆alkyl,C₁₋₆alkyl-alkoxy, CO—C₁₋₆alkyl and CO—C₁₋₆alkyl-alkoxy.

According to a First Embodiment

A and A′ are independently selected from the group consisting of an6-membered heteroaromatic ring that contains 1 nitrogen atom and a6-membered aromatic ring optionally substituted at any position with asubstituent selected from the group consisting of halogen,alkoxy-C₁₋₆alkyl, amino, amino-C₁₋₆alkyl, amino-diC₁₋₆alkyl;

R₁ is hydrogen;

R₂ is hydrogen.

According to a Second Embodiment

X₁ is selected from the group consisting of CH₂, NH and O;

X₂ is selected from the group consisting of CH₂ and NH provided that X₁and X₂ are not N at the same time;

Y is CH₂;

A is selected from the group consisting of 6-membered heteroaromaticring that contains 1 nitrogen atom in position 2 or 3 and a 6-memberedaromatic ring optionally substituted with a substituent selected fromthe group consisting of halogen and alkoxy-C₁₋₃alkyl;

A′ is selected from the group consisting of 6-membered aromatic ringoptionally substituted in meta or para positions with a substituentselected from the group consisting of halogen, alkoxy-C₁₋₆alkyl andamino-diC₁₋₆alkyl;

R₁ is hydrogen;

R₂ is hydrogen.

In a further embodiment, A is selected from the group consisting of anheteroaromatic 6-membered ring that contains 1 nitrogen atom and anunsubstituted 6-membered aromatic ring.

In a preferred embodiment, A′ is a 6-membered aromatic ring substitutedin para or meta position with a substituent selected from the groupconsisting of methoxy or an amino-di-C₁alkyl.

According to a third embodiment of the invention, the compounds ofFormula (I) can be selected from the group consisting of:

Compound number Structure  1 (ARN12405)

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

The compounds exemplified in this invention may be prepared from readilyavailable starting materials using the following general methods andprocedures for example exemplified in Michael Smith, Jerry March—March'sAdvanced Organic Chemistry: reactions mechanisms and structure—6thEdition, John Wiley & Sons Inc., 2007.

It is well known to one of ordinary skill in the art that transformationof a chemical function into another may require that one or morereactive centers in the compound containing this function be protectedin order to avoid undesired side reactions. Protection of such reactivecenters, and subsequent de-protection at the end of the synthetictransformations, can be accomplished following standard proceduresdescribed, for instance, in Theodora W. Green and Peter G. M.Wuts—Protective Groups in Organic Synthesis, Fourth Edition, John Wiley& Sons Inc., 2006.

It will be appreciated that where typical or preferred experimentalconditions (i.e. reaction temperatures, time, moles of reagents,solvents etc.) are given, other experimental conditions can also be usedunless otherwise stated. Optimum reaction conditions may vary with theparticular reactants or solvents used, but such conditions can bedetermined by the person skilled in the art, using routine optimizationprocedures.

The synthesis of a compound of Formula (I), according to the syntheticprocesses described below, can be conducted in a stepwise manner,whereby each intermediate is isolated and purified by standardpurification techniques such as, for example, column chromatography,before carrying out the subsequent reaction. Alternatively, two or moresteps of the synthetic sequence can be carried out in a so-called“one-pot” procedure, as known in the art, whereby only the compoundresulting from the two or more steps is isolated and purified.

The compounds of Formula (I), prepared with the methods described hereinbelow, may be treated or purified by conventional techniques or meansfor example by filtration, distillation, chromatography,recrystallization and combination thereof.

The salts of compounds of Formula (I) may be prepared by reacting abasic compound with the desired acid in solution.

A second aspect of the present invention is related to a pharmaceuticalcomposition comprising a compound of Formula (I) as disclosed above anda pharmaceutically acceptable carrier, stabilizer, diluent or excipientthereof.

A person skilled in the art is aware of a whole variety of such carrier,diluent or excipient compounds suitable to formulate a pharmaceuticalcomposition.

The compounds of the invention, together with a conventionally employedadjuvant, carrier, diluent or excipient may be placed into the form ofpharmaceutical compositions and unit dosages thereof, and in such formmay be employed as solids, such as tablets or filled capsules, orliquids such as solutions, suspensions, emulsions, elixirs, or capsulesfilled with the same, all for oral use, or in the form of sterileinjectable solutions for parenteral administration (includingsubcutaneous and intravenous use). Such pharmaceutical compositions andunit dosage forms thereof may comprise ingredients in conventionalproportions, with or without additional active compounds or principles,and such unit dosage forms may contain any suitable effective amount ofthe active ingredient commensurate with the intended daily dosage rangeto be employed.

Pharmaceutical compositions containing a compound of this invention canbe prepared in a manner well known in the pharmaceutical art andcomprise at least one active compound. Generally, the compounds of thisinvention are administered in a pharmaceutically effective amount. Theamount of the compound actually administered will typically bedetermined by a physician, in the light of the relevant circumstances,including the condition to be treated, the chosen route ofadministration, the actual compound administered, the age, weight, andresponse of the individual patient, the severity of the patient'ssymptoms, and the like.

The pharmaceutical compositions of the present invention can beadministered by a variety of routes including oral, rectal,subcutaneous, intravenous, intramuscular, intranasal, topical,intratumoral injection, and pulmonary routes.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. More commonly,however, the compositions are presented in unit dosage forms tofacilitate accurate dosing. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include pre-filled, pre-measured ampoules or syringes ofthe liquid compositions or pills, tablets, capsules or the like in thecase of solid compositions.

Liquid forms suitable for oral administration may include a suitableaqueous or non-aqueous vehicle with buffers, suspending and dispensingagents, colorants, flavours and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatine; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavouring agentsuch as peppermint, methyl salicylate, or orange flavouring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art.

The pharmaceutical compositions may be in the form of tablets, pills,capsules, solutions, suspensions, emulsion, powders, suppository and assustained release formulations.

If desired, tablets may be coated by standard aqueous or non-aqueoustechniques. In certain embodiments, such compositions and preparationscan contain at least 0.1 percent of active compound. The percentage ofactive compound in these compositions may, of course, be varied and mayconveniently be between about 1 percent to about 60 percent of theweight of the unit. The amount of active compound in suchtherapeutically useful compositions is such that therapeutically activedosage will be obtained. The active compounds can also be administeredintranasally as, for example, liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a bindersuch as gum tragacanth, acacia, corn starch or gelatin; excipients suchas dicalcium phosphate; a disintegrating agent such as corn starch,potato starch, alginic acid; a lubricant such as magnesium stearate; anda sweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil. Various othermaterials may be present as coatings or to modify the physical form ofthe dosage unit. For instance, tablets may be coated with shellac, sugaror both. A syrup or elixir may contain, in addition to the activeingredient, sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and a flavoring agent such as cherry or orangeflavor. To prevent breakdown during transit through the upper portion ofthe gastrointestinal tract, the composition be an enteric coatedformulation.

Topical administration of the pharmaceutical compositions is especiallyuseful when the desired treatment involves areas or organs readilyaccessible by topical application. For application topically to theskin, the pharmaceutical composition will be formulated with a suitableointment containing the active components suspended or dissolved in acarrier. Carriers for topical administration of the compounds of thisinvention include, but are not limited to, mineral oil, liquidpetroleum, white petroleum, propylene glycol, polyoxyethylenepolyoxypropylene compound, emulsifying wax and water. Alternatively, thepharmaceutical composition can be formulated with a suitable lotion orcream containing the active compound suspended or dissolved in acarrier. Suitable carriers include, but are not limited to, mineral oil,sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearylalcohol, 2-octyldodecanol, benzyl alcohol and water.Topically-transdermal patches and iontophoretic administration are alsodescribed.

Compositions for pulmonary administration include, but are not limitedto, dry powder compositions consisting of the powder of a compound ofFormula (I) or a salt thereof, and the powder of a suitable carrierand/or lubricant. The compositions for pulmonary administration can beinhaled from any suitable dry powder inhaler device known to a personskilled in the art.

The compounds of this invention can also be administered by intratumoralinjection, or injection directly into the tumor vasculature. Local,regional or systemic administration also may be appropriate. For tumorsof >4 cm, the volume to be administered will be about 4-10 ml(preferably 10 ml), while for tumors of <4 cm, a volume of about 1-3 mlwill be used (preferably 3 ml). Multiple injections delivered as singledose comprise about 0.1 to about 0.5 ml volumes. In the case of surgicalintervention, the present invention may be used preoperatively, torender an inoperable tumor subject to resection.

Administration of the compositions is performed under a protocol and ata dosage sufficient to reduce the inflammation and pain in the subject.In some embodiments, in the pharmaceutical compositions of the presentinvention the active principle or active principles are generallyformulated in dosage units. The dosage unit may contain from 0.1 to 1000mg of a compound of Formula (I) per dosage unit for dailyadministration.

In some embodiments, the amounts effective for a specific formulationwill depend on the severity of the disease, disorder or condition,previous therapy, the individual's health status and response to thedrug. In some embodiments, the dose is in the range from 0.001% byweight to about 60% by weight of the formulation.

When used in combination with one or more other active ingredients, thecompound of the present invention and the other active ingredient may beused in lower doses than when each is used singly.

Concerning formulations with respect to any variety of routes ofadministration, methods and formulations for the administration of drugsare disclosed in Remington's Pharmaceutical Sciences, 17th Edition,Gennaro et al. Eds., Mack Publishing Co., 1985, and Remington'sPharmaceutical Sciences, Gennaro Ark. ed. 20th Edition, 2000, Williams &Wilkins Pa., USA, and Remington: The Science and Practice of Pharmacy,21st Edition, Lippincott Williams & Wilkins Eds., 2005; and in Ansel'sPharmaceutical Dosage Forms and Drug Delivery Systems, 8th Edition,Lippincott Williams & Wilkins Eds., 2005.

The above described components for orally administered or injectablecompositions are merely representative.

The compounds of this invention can also be administered in sustainedrelease forms or from sustained release drug delivery systems.

The compounds of formula (I) may be used as a stand-alone therapeuticagent, or in combination with other chemotherapeutics having differentmode of actions. The preferred combining chemotherapeutic agents isselected from the group consisting of cisplatin, carboplatin,nedaplatin, oxaliplatin, satraplatin, triplatin tetra nitrate, as wellas non-classical alkylating agents like dacarbazine and temozolamide.The compounds of formula (I) may also be used in combination withradiation therapy.

A third aspect of the present invention is related to the use ofcompounds of Formula (I) as disclosed above or the pharmaceuticalcomposition thereof, or their pharmaceutically acceptable salts orsolvates as a medicament.

In particular, compounds of Formula (I) can be used in the treatment ofdiseases or disorders associated to increased (relative to physiologicalor desired) RhoJ/Cdc42 levels of expression or function. In particular,the compounds of formula (I) may act as inhibitors of the RhoJ-PAK, moreparticularly they may be used in the treatment of primary and metastaticneoplastic diseases, pre-malignant conditions, such as hyperplasia,metaplasia or dysplasia, cancer, cancer metastasis, benign tumors,hyperproliferative disorders, cardiomyopathies and retinal disorders.Preferably, the compounds of formula (I) are used in the treatment ofmelanoma.

In the following, the present invention shall be illustrated by means ofsome examples, which are not construed to be viewed as limiting thescope of the invention.

The following abbreviations are hereinafter used in the accompanyingexamples: acetic acid (AcOH), acetonitrile (ACN), ammonia (NH₃),deuterated chloroform (CDCl₃), deuterated dimethylsulfoxide (DMSO-d₆),dichloromethane (DCM), diethyl ether (Et₂O), dimethylsulfoxide (DMSO),ethanol (EtOH), ethyl acetate (AcOEt), hydrochloric acid (HCl),tert-butylmethyl ether (TBME), methanol (MeOH), room temperature (rt),sodium bicarbonate (NaHCO₃), sodium hydroxide (NaOH), sodium sulphate(Na₂SO₄), dichloro[1,1′-bis(diphenylphosphino)ferrocene] palladiumdichloromethane complex (PdCl₂(dppf) dichloromethane complex), water(H₂O).

Chemicals, Materials and Methods

Synthesis

All the commercial available reagents and solvents were used aspurchased from vendors without further purification. Dry solvents werepurchased from Sigma-Aldrich. Automated column chromatographypurifications were done using a Teledyne ISCO apparatus (CombiFlash® Rf)with pre-packed silica gel columns of different sizes (from 4 g up to120 g) and mixtures of increasing polarity of cyclohexane and ethylacetate (AcOEt), cyclohexane and tert-butylMethyl eter (TBME) ordicloromethane (DCM) and methanol (MeOH).

Characterizations

NMR experiments were run on a Bruker Avance III 400 system (400.13 MHzfor ¹H), equipped with a BBI probe and Z-gradients. Spectra wereacquired at 300 K, using deuterated dimethylsulfoxide (DMSO-d₆) ordeuterated chloroform (CDCl₃) as solvents. For ¹H-NMR, data are reportedas follows: chemical shift, multiplicity (s=singlet, d=doublet,dd=double of doublets, t=triplet, q=quartet, m=multiplet), couplingconstants (Hz) and integration. UPLC/MS analyses were run on a WatersACQUITY UPLC/MS system consisting of a SQD (single quadrupole detector)mass spectrometer equipped with an electrospray ionization interface anda photodiode array detector. The PDA range was 210-400 nm. Analyses wereperformed on an ACQUITY UPLC BEH C18 column (100×2.1 mmID, particle size1.7 μm) with a VanGuard BEH C18 pre-column (5×2.1 mmID, particle size1.7 μm). Mobile phase was 10 mM NH₄OAc in H₂O at pH 5 adjusted withCH₃COOH (A) and 10 mM NH₄OAc in CH₃CN—H₂O (95:5) at pH 5.0. For analysismethod 1, mobile-phase B proportion increased from 5% to 95% in 3minutes. For analysis method 2, mobile-phase B proportion increased from50% to 100% in 3 min. Electrospray ionization in positive and negativemode was applied. ESI was applied in positive and negative mode. Alltested compounds showed ≥90% purity by NMR and UPLC/MS analysis.

PREPARATIONS AND EXAMPLES

Reaction A. Phenylboronic acid (1 eq), K₂CO₃ 2M (2 eq), PdCl₂(dppf).DCM(0.05 eq), 1,4-dioxane, 60° C., microwave, Ar, 1 h, Yield=72%. ReactionB. Aniline derivative (1 eq), Pd(OAc)₂ (0.05 eq), racBINAP (0.05 eq),Cs₂CO₃ (1.2 eq), 1,4-diaxane, Ar, 60° C., microwave, 4 h. Reaction C.4,4,5,5-tetramethylboronate (1.2 eq), K₂CO₃, 2M (2 eq), PdCl₂(dppf).DCM(0.05 eq), 1,4-dioxane, 120° C., microwave, Ar, 2 h. Reactions D and E′.HCOONH₄ (4 eq), Pd(OH)₂/C (20% weight), MeOH, reflux, N₂, 4 h, or H-cubeapparatus (Pd(OH)₂ cartridge, 50° C., 50 bar). Reaction D′ and E. HCl(4M), 1,4-dioxane, 0° C. to rt, 1 h.

Reaction 1. 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (1.1 eq), LDA 2MTHF/heptane/ethylbenzene (1.2 eq), THF (dry), −78° C. to rt, Ar, 16 h,yield 28%. Reaction 2. Bispinacolatodiboron (1.3 eq), KOAc (2.8 eq),PdCl₂ (dppf).DCM (0.1 eq), 1,4-dioxane, 80° C., Ar, 3 h, yield 800.

General Procedure Reaction B. Palladium Catalyzed Aniline DerivativesCoupling.

A mixture of Pd(OAc)₂ (0.05 mmol) and racBINAP (0.05 mmol) in1,4-dioxane (3 ml) was stirred under Ar flushing for 10 minutes. Thenwere stepwise added a solution of intermediate A (1 mmol) in 1,4-dioxane(1 ml), a solution of corresponding substituted aniline (1 mmol) in1,4-dioxane (1 ml) and Cs₂CO₃ (1.2 mmol). The reaction mixture wasstirred in a CEM® microwave apparatus at 60° C. for 4 hours, filtratedthrough a celite coarse patch, rinsed with DCM and concentrated todryness at low pressure. Final normal phase purification yieldedIntermediate B.n.

General Procedure Reaction C. Suzuki Coupling Reaction.

A suspension of compound obtained from general procedure B (1 mmol),corresponding 4,4,5,5-tetramethylboronate (1.2 mmol), PdCl₂(dppf)dichloromethane complex (0.1 mmol) and K₂CO₃ 2M solution (2 mmol) in1,4-dioxane (10 ml) was stirred in a CEM® microwave apparatus at 120° C.for 2 hours. Resulting crude was portioned between dichloromethane (25ml), NaHCO₃ saturated solution (25 ml), the organic layer dried overNa₂SO₄ and concentrated to dryness at low pressure. Final normal phasepurification yielded Intermediate C.n.

General Procedure Reaction D and E′. Double Bound Reduction.

Method 1. Under N₂ atmosphere, a suspension of compound to be reduced (1mmol), ammonium formate (4 mmol), Pd(OH)₂/C (20% of starting materialweight) was stirred at reflux temperature until reaction completion.Catalyst was filtered off through a celite coarse patch and resultingfiltrate concentrated to dryness at low pressure. Final normal phasepurification yielded Intermediate D.n.

Method 2. A starting material 0.01 M solution in MeOH or THF was elutedin a H-cube apparatus through a Pd(OH)₂—C cartridge at 50° C. under 50bar H₂ pressure until reaction completion. Final normal phasepurification yielded Intermediate D′.n.

General Procedure Reaction D′ and E. Boc Elimination.

To a 0° C. solution of Boc protected compound (1 mmol) in 1,4-dioxane(2.6 ml) was dropwise added a HCl (4M) solution in 1,4-dioxane (2.6 ml,10 mmol) and the reaction mixture stirred at room temperature for 1 h,then the reaction crude was concentrated to dryness at low pressure, theresulting crude portioned between DCM (20 ml) and NaOH 0.1 M (20 ml),the organic layer dried over Na₂SO₄ and concentrated to dryness at lowpressure. Final normal phase purification yielded the compounds of theinvention.

Example 1.N1,N1-dimethyl-N4-[6-phenyl-2-(3-piperidyl)pyrimidin-4-yl]benzene-1,4-diamine(compound 8)

Step 1. Synthesis of 2,4-dichloro-6-phenyl-pyrimidine (Intermediate A)

A suspension of 2,4,6-trichloropyrimidine (1000 mg, 5.29 mmol), phenylboronic acid (665 mg, 5.29 mmol), PdCl₂(dppf) dichloromethane complex(204 mg, 0.26 mmol) and K₂CO₃ 2 M solution (5.3 ml, 10.58 mmol) in1,4-dioxane (26.4 ml) was stirred in a CEM® microwave apparatus at 60°C. for 1 hour. Resulting crude was portioned between dichloromethane(150 ml), NaHCO₃ saturated solution (100 ml), the organic layer driedover Na₂SO₄ and concentrated to dryness at low pressure. Final normalphase purification (cyclohexane/DCM from 100/0 to 85/15) afforded puretitle compound (857 mg, yield 72%). Rt=1.38 min (analysis method 2); MS(ESI) m/z: 225.1 [M-H]⁺, [M-H]⁺ calculated: 225.0. ¹H NMR (400 MHz,CDCl₃) δ 8.13-8.03 (m, 2H), 7.68 (s, 1H), 7.62-7.48 (m, 3H).

Step 2. Synthesis ofN1-(2-chloro-6-phenyl-pyrimidin-4-yl)-N4,N4-dimethyl-benzene-1,4-diamine(Intermediate B.1)

Titled compound was obtained using intermediate A (300 mg, 1.33 mmol)and N1,N1-dimethylbenzene-1,4-diamine (191.1 mg, 1.33 mmol) followingthe general procedure reaction B previously described. Final normalphase purification (cyclohexane/TBME from 100/0 to 80/20) afforded puretitle compound (272 mg, yield 63%). Rt=1.56 min (analysis method 2); MS(ESI) m/z: 325.1 [M-H]⁺, [M-H]⁺ calculated: 325.1. ¹H NMR (400 MHz,DMSO-d₆) δ 9.76 (s, 1H), 7.93 (dd, J=6.7, 3.0 Hz, 2H), 7.52 (dd, J=4.6,2.4 Hz, 3H), 7.36 (s, 2H), 7.00 (s, 1H), 6.87-6.64 (m, 2H), 2.89 (s,6H).

Step 3. Synthesis of tert-butyl 5-(trifluoromethylsulfonyloxy)-3,4-dihydro-2H-pyridine-1-carboxylate (Intermediate1)

At −78° C., to a solution of lithium diisopropylamide 2.0 M incyclohexane (8.8 ml, 17.53 mmol) in dry tetrahydrofurane (15.6 ml) wasadded drop wise a solution of 3-oxo-piperidine-1-carboxyilic acidtert-butyl ester (3000 mg, 14.60 mmol) in dry tetrahydrofurane (15.6mL). The mixture was stirred at −78° C. for 1 h and a solution ofN-phenyl bis trifluoromethanesulfonamide (5855.6 mg, 16.07 mmol) in drytetrahydrofurane (15.8 mL) was added. The mixture was stirred at −78° C.for 2 h and then was allowed to warm up to room temperature and stirred16 additional hours at room temperature. The mixture was evaporated todryness and the residue was taken with diethyl ether (50 ml), washedwith water (50 mL), a 2 M solution of sodium hydroxide (50 mL) and brine(50 mL), dried over sodium sulfate and concentrated to dryness at lowpressure. Final normal phase purification (cHexane/DCM from 100/0 to50/50) afforded pure title compound (1354 mg, 28% yield). Rt=2.66 min(analysis method 1). ¹H NMR (400 MHz, CDCl₃) δ 7.07 (s, 1H), 3.52 (s,2H), 2.43 (td, J=6.4, 1.5 Hz, 2H), 1.93 (tt, J=6.3, 5.0 Hz, 2H), 1.49(s, 9H).

Step 4. Synthesis of tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-pyridine-1-carboxylate(Intermediate 2)

To a degassed solution of intermediate 1 (600 mg, 1.81 mmol) in dioxane(10.7 ml) was added bis-(pinacolato)diboron (603.8 mg, 2.35 mmol),potassium acetate (502.7 mg, 5.07 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene] palladium dichloromethane complex (139.5 mg, 0.18 mmol) were added. The mixture wasstirred at 80° C. for 3 h. After cooling down, the mixture was filteredand resulting filtrate concentrated to dryness at low pressure. Finalnormal phase purification (cHexane/DCM from 70/30 to 50/50) affordedpure title compound (448 mg, 80% yield). Rt=1.85 min (analysis method2). MS (ESI) m/z 310.2 [M-H]⁺, [M-H]⁺ calculated: 310.2. ¹H NMR (400MHz, CDCl₃) δ 5.29 (s, 1H), 3.67-3.39 (m, 2H), 2.15-1.96 (m, 2H),1.81-1.73 (m, 2H), 1.49 (s, 9H), 1.32-1.17 (m, 12H).

Step 5. Synthesis of tert-butyl5-[4-[4-(dimethylamino)anilino]-6-phenyl-pyrimidin-2-yl]-3,4-dihydro-2H-pyridine-1-carboxylate(Intermediate C.1)

Titled compound was obtained using intermediate B.1 (100 mg, 0.35 mmol)and intermediate 2 (117.8 mg, 0.37 mmol) following the general procedurereaction C previously described. Final normal phase purification(cyclohexane/AcOEt from 100/0 to 85/15) afforded pure title compound(107.4 mg, yield 74%). Rt=2.58 min (analysis method 2); MS (ESI) m/z472.4 [M-H]⁺, [M-H]⁺ calculated: 472.3. ¹H NMR (400 MHz, DMSO-d₆) δ 9.28(s, 1H), 8.12-7.96 (m, 2H), 7.64-7.42 (m, 5H), 7.15 (s, 1H), 6.96 (s,1H), 6.86-6.69 (m, 2H), 4.11 (d, J=4.0 Hz, 2H), 3.55 (t, J=5.7 Hz, 2H),2.87 (s, 6H), 2.67 (d, J=7.0 Hz, 2H), 1.44 (s, 9H).

Step 6. Synthesis of tert-butyl3-[4-[4-(dimethylamino)anilino]-6-phenyl-pyrimidin-2-yl]piperidine-1-carboxylate(Intermediate D.1)

Titled compound was obtained using intermediate C.1 (60.5 mg, 0.12 mmol)following the general procedure D method 2 previously described. Finalnormal phase purification (cHexane/TBME from 90/10 to 70:30) affordedpure title compound (60 mg, yield 99%). Rt=2.22 min (analysis method 2);MS (ESI) m/z: 474.4 [M-H]⁺, [M-H]⁺ calculated: 474.3. ¹H NMR (400 MHz,DMSO-d₆) δ 9.38 (s, 1H), 8.24-7.80 (m, 2H), 7.59-7.34 (m, 5H), 6.98 (s,1H), 6.91-6.59 (m, 2H), 3.37 (d, J=9.8 Hz, 1H), 3.16-3.02 (m, 1H),3.02-2.91 (m, 2H), 2.87 (s, 6H), 2.68 (td, J=11.9, 3.0 Hz, 1H),2.23-2.05 (m, 1H), 1.89-1.70 (m, 2H), 1.63 (q, J=12.8 Hz, 1H), 1.45 (s,9H).

Step 7. Synthesis ofN1,N1-dimethyl-N4-[6-phenyl-2-(3-piperidyl)pyrimidin-4-yl]benzene-1,4-diamine(Compound 8)

Titled compound was obtained using intermediate D.1 (61 mg, 0.13 mmol)following the general procedure reaction E previously described. Finalnormal phase purification (DCM/DCM:NH₃ 1M MeOH 4:1 from 80/20 to 60/40)afforded pure title compound (46 mg, yield 95%). Rt=1.96 min (analysismethod 1); MS (ESI) m/z: 374.6 [M-H]⁺, [M-H]⁺ calculated: 374.2. ¹H NMR(400 MHz, DMSO-d₆) δ 9.38 (s, 1H), 8.24-7.80 (m, 2H), 7.59-7.34 (m, 5H),6.98 (s, 1H), 6.91-6.59 (m, 2H), 3.37 (d, J=9.8 Hz, 1H), 3.16-3.02 (m,1H), 3.02-2.91 (m, 2H), 2.87 (s, 6H), 2.68 (td, J=11.9, 3.0 Hz, 1H),2.23-2.05 (m, 1H), 1.89-1.70 (m, 2H), 1.63 (q, J=12.8 Hz, 1H).

Example 2. N-(4-methoxyphenyl)-6-phenyl-2-(3-piperidyl)pyrimidin-4-amine (Compound 9)

Step 1. Synthesis of2-chloro-N-(4-methoxyphenyl)-6-phenyl-pyrimidin-4-amine (IntermediateB.2)

Titled compound was obtained using intermediate A (100 mg, 0.44 mmol)and p-methoxyaniline (55.2 mg, 0.44 mmol) following the generalprocedure reaction B previously described. Final normal phasepurification (cyclohexane/TBME from 95/5 to 75/25) afforded pure titlecompound (86.8 mg, yield 63%). Rt=1.39 min (analysis method 2); MS (ESI)m/z: 312.1 [M-H]⁺, [M-H]⁺ calculated: 312.1. ¹H NMR (400 MHz, DMSO-d₆) δ9.91 (s, 1H), 8.06-7.84 (m, 2H), 7.65-7.37 (m, 5H), 7.06 (s, 1H),7.02-6.92 (m, 2H), 3.76 (s, 3H).

Step 2. Synthesis of tert-butyl5-[4-(4-methoxyanilino)-6-phenyl-pyrimidin-2-yl]-3,4-dihydro-2H-pyridine-1-carboxylate(Intermediate C.2)

Titled compound was obtained using intermediate B.2 (100 mg, 0.32 mmol)and intermediate 2 (119.0 mg, 0.38 mmol) following the general procedureC previously described. Final normal phase purification(cyclohexane/AcOEt from 100/0 to 80/20) afforded pure title compound(64.7 mg, yield 44%). Rt=2.37 min (analysis method 2); MS (ESI) m/z459.6 [M-H]⁺, [M-H]⁺ calculated: 459.2. ¹H NMR (400 MHz, CDCl₃) δ8.05-7.97 (m, 2H), 7.46-7.37 (m, 3H), 7.31 (t, J=6.5 Hz, 2H), 6.98-6.90(m, 2H), 6.71 (s, 1H), 6.68-6.46 (m, 1H), 3.84 (s, 3H), 3.66 (d, J=9.5Hz, 2H), 2.82-2.60 (m, 2H), 2.02-1.86 (m, 2H), 1.56 (s, 9H).

Step 3. Synthesis of tert-butyl3-[4-(4-methoxyanilino)-6-phenyl-pyrimidin-2-yl]piperidine-1-carboxylate(Intermediate D.2)

Titled compound was obtained using intermediate C.2 (65.0 mg, 0.14 mmol)following the general procedure reaction D method 2 previouslydescribed. Final normal phase purification (cHexane/TBME from 100/0 to80/20) afforded pure title compound (40 mg, yield 62%). Rt=1.94 min(analysis method 2); MS (ESI) m/z: 461.2 [M-H]⁺, [M-H]⁺ calculated:461.2. ¹H NMR (400 MHz, CDCl₃) δ 8.07-7.80 (m, 2H), 7.46-7.38 (m, 3H),7.26 (s, 1H), 7.01-6.89 (m, 2H), 6.77 (s, 1H), 6.71 (s, 1H), 3.84 (s,3H), 3.01-2.68 (m, 2H), 2.23 (d, J=12.3 Hz, 1H), 1.80 (qd, J=13.0, 3.8Hz, 2H), 1.73-1.52 (m, 4H), 1.47 (s, 9H).

Step 4. Synthesis ofN-(4-methoxyphenyl)-6-phenyl-2-(3-piperidyl)pyrimidin-4-amine (Compound9)

Titled compound was obtained using intermediate D.2 (40 mg, 0.09 mmol)following the general procedure reaction E previously described. Finalnormal phase purification (DCM/DCM:NH₃ 1M MeOH 4:1 from 85/15 to 65:35)afforded pure title compound (31 mg, yield 99%). Rt=0.49 min (analysismethod 2); MS (ESI) m/z: 361.6 [M-H]⁺, [M-H]⁺ calculated: 361.2. ¹H NMR(400 MHz, DMSO-d₆) δ 9.60 (s, 1H), 8.15-7.90 (m, 2H), 7.59 (d, J=8.4 Hz,2H), 7.56-7.47 (m, 3H), 7.05 (d, J=4.2 Hz, 1H), 7.00-6.90 (m, 2H), 3.76(s, 3H), 3.60 (d, J=11.9 Hz, 1H), 3.33-3.11 (m, 3H), 2.96-2.91 (m, 1H),2.26-2.19 (m, 1H), 1.97-1.65 (m, 2H).

Example 3. N3,N3-dimethyl-N1-[6-phenyl-2-(3-piperidyl)pyrimidin-4-yl]benzene-1,3-diamine (Compound 10)

Step 1. Synthesis ofN1-(2-chloro-6-phenyl-pyrimidin-4-yl)-N3,N3-dimethyl-benzene-1,3-diamine(Intermediate B.3)

Titled compound was obtained using intermediate A (300 mg, 1.13 mmol)and N1,N1-dimethylbenzene-1,3-diamine (181.5 mg, 1.33 mmol) followingthe general procedure reaction B previously described. Final normalphase purification (cyclohexane/TBME from 100/0 to 80/20) afforded puretitle compound (246 mg, yield 57%). Rt=1.73 min (analysis method 2); MS(ESI) m/z: 325.1 [M-H]⁺, [M-H]⁺ calculated: 325.1. ¹H NMR (400 MHz,DMSO-d₆) δ 9.93 (s, 1H), 8.14-7.82 (m, 2H), 7.60-7.47 (m, 3H), 7.29-7.09(m, 2H), 7.04 (s, 1H), 6.99-6.85 (m, 1H), 6.51 (ddd, J=8.4, 2.5, 0.8 Hz,1H), 2.92 (s, 6H).

Step 2. Synthesis of tert-butyl5-[4-[3-(dimethylamino)anilino]-6-phenyl-pyrimidin-2-yl]-3,4-dihydro-2H-pyridine-1-carboxylate(Intermediate C.3)

Titled compound was obtained using intermediate B.3 (175 mg, 0.54 mmol)and intermediate 2 (199.9 mg, 0.65 mmol) following the general procedurereaction C previously described. Final normal phase purification(cyclohexane/AcOEt from 100/0 to 85/15) afforded pure title compound(109.2 mg, yield 43%). Rt=2.65 min (analysis method 2); MS (ESI) m/z472.3 [M-H]⁺, [M-H]⁺ calculated: 472.3. ¹H NMR (400 MHz, DMSO-d₆) δ 9.34(s, 1H), 8.40 (s, 1H), 8.04 (dd, J=7.7, 1.9 Hz, 2H), 7.59-7.44 (m, 4H),7.11 (t, J=8.0 Hz, 2H), 6.99 (s, 1H), 6.40 (dd, J=9.1, 2.5 Hz, 1H), 3.59(t, J=5.6 Hz, 2H), 2.92 (s, 6H), 2.65-2.59 (m, 2H), 1.88 (p, J=6.0 Hz,2H), 1.50 (s, 9H).

Step 3. Synthesis of tert-butyl3-[4-[3-(dimethylamino)anilino]-6-phenyl-pyrimidin-2-yl]piperidine-1-carboxylate(Intermediate D.3)

Titled compound was obtained using intermediate C.3 (105 mg, 0.22 mmol)following the general procedure reaction D method previously described.Final normal phase purification (cHexane/AcOEt from 100/0 to 80/20)afforded pure title compound (12 mg, yield 12%). Rt=2.35 min (analysismethod 2); MS (ESI) m/z: 474.6 [M-H]⁺, [M-H]⁺ calculated: 474.3. ¹H NMR(400 MHz, CDCl₃) δ 8.04-7.93 (m, 2H), 7.49-7.37 (m, 4H), 7.04 (s, 1H),6.78 (s, 1H), 6.69 (d, J=7.7 Hz, 1H), 6.59 (d, J=8.5 Hz, 1H), 4.20-4.08(m, 1H), 3.23-3.16 (m, 1H), 2.99 (s, 6H), 2.98-2.91 (m, 1H), 2.88-2.77(m, J=14.3 Hz, 1H), 2.31-2.20 (m, 1H), 1.82-1.58 (m, 2H), 1.51-1.45 (m,11H).

Step 4. Synthesis ofN3,N3-dimethyl-N1-[6-phenyl-2-(3-piperidyl)pyrimidin-4-yl]benzene-1,3-diamine(Compound 10)

Titled compound was obtained using intermediate D.3 (34 mg, 0.08 mmol)following the general procedure reaction E. Final normal phasepurification (DCM/DCM:NH₃ 1M MeOH 4:1 from 95/5 to 45/55) afforded puretitle compound (16 mg, yield 61%). Rt=2.07 min (analysis method 1); MS(ESI) m/z: 374.5 [M-H]⁺, [M-H]⁺ calculated: 374.2. ¹H NMR (400 MHz,DMSO-d₆) δ 9.50 (s, 1H), 8.01 (dd, J=7.8, 1.8 Hz, 2H), 7.56-7.48 (m,3H), 7.46 (s, 1H), 7.12 (t, J=8.1 Hz, 1H), 7.10-7.06 (m, 1H), 6.90 (d,J=8.0 Hz, 1H), 6.40 (dd, J=8.2, 2.5 Hz, 1H), 3.28-3.14 (m, 1H), 2.94 (s,6H), 2.94-2.87 (m, 1H), 2.84-2.75 (m, 2H), 2.46 (dd, J=12.1, 2.9 Hz,1H), 2.16-2.03 (m, 1H), 1.90-1.72 (m, 1H), 1.71-1.58 (m, 1H), 1.57-1.39(m, 1H).

Example 4. N-(3-methoxyphenyl)-6-phenyl-2-(3-piperidyl)pyrimidin-4-amine (Compound 11)

Step 1. Synthesis of2-chloro-N-(3-methoxyphenyl)-6-phenyl-pyrimidin-4-amine (IntermediateB.4)

Titled compound was obtained using intermediate A (300 mg, 1.13 mmol)and m-methoxyaniline (154 μl, 1.33 mmol) following the general procedurereaction B previously described. Final normal phase purification(cyclohexane/TBME from 100/0 to 85/15) afforded pure title compound (150mg, yield 36%). Rt=1.52 min (analysis method 2); MS (ESI) m/z: 312.1[M-H]⁺, [M-H]⁺ calculated: 312.1. ¹H NMR (400 MHz, DMSO-d₆) δ 10.07 (s,1H), 8.00-7.90 (m, 2H), 7.59-7.50 (m, 3H), 7.34 (t, J=2.3 Hz, 1H), 7.29(t, J=8.1 Hz, 1H), 7.18 (s, 2H), 6.69 (ddd, J=8.2, 2.5, 0.9 Hz, 1H),3.77 (s, 3H).

Step 2. Synthesis of tert-butyl5-[4-(3-methoxyanilino)-6-phenyl-pyrimidin-2-yl]-3,4-dihydro-2H-pyridine-1-carboxylate(Intermediate C.4)

Titled compound was obtained using intermediate B.4 (100 mg, 0.32 mmol)and intermediate 2 (119.0 mg, 0.38 mmol) following the general procedurereaction C previously described. Final normal phase purification(cyclohexane/TBME from 100/0 to 80/20) afforded pure title compound(65.0 mg, yield 44%).

Rt=2.40 min (method 2); MS (ESI) m/z 459.6 [M-H]⁺, [M-H]⁺ calculated:459.2.

Step 3. Synthesis of tert-butyl3-[4-(3-methoxyanilino)-6-phenyl-pyrimidin-2-yl]piperidine-1-carboxylate(Intermediate D.4)

Titled compound was obtained using intermediate C.4 (65.0 mg, 0.14 mmol)following the general procedure reaction D method 2 previouslydescribed. Final normal phase purification (cHexane/AcOEt from 100/0 to80:20) afforded pure title compound (32.6 mg, yield 50%). Rt=2.13 min(analysis method 2); MS (ESI) m/z: 461.6 [M-H]⁺, [M-H]⁺ calculated:461.2. ¹H NMR (400 MHz, CDCl₃) δ 8.04-7.92 (m, 2H), 7.45 (p, J=3.9, 3.2Hz, 3H), 7.30 (t, J=8.1 Hz, 1H), 7.08 (t, J=2.2 Hz, 1H), 6.99 (s, 1H),6.95 (dd, J=7.9, 2.0 Hz, 1H), 6.89 (s, 1H), 6.72 (dd, J=8.3, 2.4 Hz,1H), 3.84 (s, 3H), 3.20 (s, 1H), 2.99-2.88 (m, 1H), 2.80 (t, J=12.5 Hz,1H), 2.26 (d, J=12.5 Hz, 1H), 1.93-1.74 (m, 2H), 1.75-1.51 (m, 3H), 1.47(s, 9H).

Step 4. Synthesis ofN-(3-methoxyphenyl)-6-phenyl-2-(3-piperidyl)pyrimidin-4-amine (Compound11)

Titled compound was obtained using intermediate D.4 (61 mg, 0.13 mmol)following the general procedure reaction E. Final normal phasepurification (DCM/DCM:NH₃ 1M MeOH 4:1 from 85/15 to 60/40) afforded puretitle compound (39 mg, yield 82%). Rt=1.91 min (analysis method 1); MS(ESI) m/z: 361.6 [M-H]⁺, [M-H]⁺ calculated: 361.2. ¹H NMR (400 MHz,DMSO-d₆) δ 9.89 (s, 1H), 8.17-7.94 (m, 2H), 7.67-7.44 (m, 4H), 7.34-7.12(m, 3H), 6.61 (dt, J=5.4, 2.4 Hz, 1H), 3.79 (s, 3H), 3.63 (d, J=8.1 Hz,1H), 3.27-3.18 (m, 3H), 2.89 (d, J=14.1 Hz, 1H), 2.26 (d, J=11.7 Hz,1H), 2.01-1.67 (m, 3H).

Example 5. N4,N4-dimethyl-N1-[6-phenyl-2-(4-piperidyl)pyrimidin-4-yl]benzene-1,4-diamine (Compound 12)

Step 1. Synthesis of tert-butyl 4-[4-[4-(dimethylamino)anilino]-6-phenyl-pyrimidin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate(Intermediate C.5)

Titled compound was obtained using intermediate B.1 (100 mg, 0.35 mmol)and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate(117.8 mg, 0.37 mmol) following the general procedure reaction Cpreviously described. Final normal phase purification (cyclohexane/AcOEtfrom 100/0 to 85/15) afforded pure title compound (107.4 mg, yield 74%).Rt=2.58 min (analysis method 2); MS (ESI) m/z 472.4 [M-H]⁺, [M-H]⁺calculated: 472.3. ¹H NMR (400 MHz, DMSO-d₆) δ 9.28 (s, 1H), 8.12-7.96(m, 2H), 7.64-7.42 (m, 5H), 7.15 (s, 1H), 6.96 (s, 1H), 6.86-6.69 (m,2H), 4.11 (d, J=4.0 Hz, 2H), 3.55 (t, J=5.7 Hz, 2H), 2.87 (s, 6H), 2.67(d, J=7.0 Hz, 2H), 1.44 (s, 9H).

Step 2. Synthesis ofN4,N4-dimethyl-N1-[6-phenyl-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-yl]benzene-1,4-diamine(Intermediate D′.5)

Titled compound was obtained using intermediate C.5 (106 mg, 0.22 mmol)following the general procedure reaction D′ (84 mg, yield 99%). Rt=0.72min (analysis method 2); MS (ESI) m/z: 372.5 [M-H]⁺, [M-H]⁺ calculated:372.2. Resulting solid was used in next step without any furtherpurification procedure.

Step 3. Synthesis ofN4,N4-dimethyl-N1-[6-phenyl-2-(4-piperidyl)pyrimidin-4-yl]benzene-1,4-diamine(Compound 12)

Titled compound was obtained using intermediate D′0.5 (84 mg, 0.22 mmol)following the general procedure reaction E′ method previously described.Final normal phase purification (DCM/DCM:NH₃ 1M MeOH 4:1 from 70/30 to50/50) afforded pure title compound (54 mg, yield 64%). Rt=1.98 min(analysis method 1); MS (ESI) m/z: 374.2 [M-H]⁺, [M-H]⁺ calculated:374.2. ¹H NMR (400 MHz, DMSO-d₆). δ 9.25 (s, 1H), 8.17-7.82 (m, 2H),7.69-7.37 (m, 5H), 6.93 (s, 1H), 6.83-6.66 (m, 2H), 3.08 (dt, J=12.2,3.4 Hz, 2H), 2.87 (s, 6H), 2.77 (tt, J=11.5, 3.8 Hz, 1H), 2.66 (td,J=12.1, 2.6 Hz, 2H), 1.93 (dd, J=13.4, 3.5 Hz, 2H), 1.77 (qd, J=13.0,12.5, 4.0 Hz, 2H).

Example 6. N-(4-methoxyphenyl)-6-phenyl-2-(4-piperidyl)pyrimidin-4-amine (Compound 13)

Step 1. Synthesis of tert-butyl4-[4-(4-methoxyanilino)-6-phenyl-pyrimidin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate(Intermediate C.6)

Titled compound was obtained using intermediate B.2 (80 mg, 0.26 mmol)and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate(98.1 mg, 0.31 mmol) following the general procedure reaction Cpreviously described. Final normal phase purification (cyclohexane/AcOEtfrom 95/5 to 75/25) afforded pure title compound (104.7 mg, yield 89%).Rt=2.24 min (analysis method 2); MS (ESI) m/z 459.3 [M-H]⁺, [M-H]⁺calculated: 459.2. ¹H NMR (400 MHz, DMSO-d₆) δ 9.44 (s, 1H), 8.12-8.02(m, 2H), 7.68-7.60 (m, 2H), 7.58-7.46 (m, 3H), 7.17 (s, 1H), 7.01 (s,1H), 6.99-6.92 (m, 2H), 4.12 (s, 2H), 3.75 (s, 3H), 3.56 (t, J=5.7 Hz,2H), 2.68 (q, J=4.0, 3.4 Hz, 2H), 1.44 (s, 9H).

Step 2. Synthesis ofN-(4-methoxyphenyl)-6-phenyl-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-amine(Intermediate D′.6)

Titled compound was obtained using intermediate C.6 (102 mg, 0.22 mmol)following the general procedure reaction D′ (80 mg, yield 99%). Rt=0.60min (analysis method 2); MS (ESI) m/z: 359.2 [M-H]⁺, [M-H]⁺ calculated:359.2. Resulting solid was used in next step without any furtherpurification procedure.

Step 3. Synthesis ofN-(4-methoxyphenyl)-6-phenyl-2-(4-piperidyl)pyrimidin-4-amine (Compound13)

Titled compound was obtained using intermediate D′0.6 (80 mg, 0.22 mmol)following the general procedure reaction E′ method previously described.Final normal phase purification (DCM/DCM:NH₃ 1M MeOH 4:1 from 85/15 to50/50) afforded pure title compound (52.5 mg, yield 64%). Rt=1.87 min(analysis method 1); MS (ESI) m/z: 361.3 [M-H]⁺, [M-H]⁺ calculated:361.2. ¹H NMR (400 MHz, DMSO-d₆). δ 9.44 (s, 1H), 8.14-7.89 (m, 2H),7.64 (d, J=8.9 Hz, 2H), 7.58-7.38 (m, 3H), 6.99 (s, 1H), 6.96-6.91 (m,2H), 3.75 (s, 3H), 3.13 (d, J=12.4 Hz, 2H), 2.83 (tt, J=11.4, 3.8 Hz,1H), 2.73 (td, J=12.2, 2.7 Hz, 2H), 1.97 (dd, J=12.8, 3.4 Hz, 2H), 1.81(qd, J=12.2, 4.0 Hz, 2H).

Example 7. N3,N3-dimethyl-N1-[6-phenyl-2-(4-piperidyl)pyrimidin-4-yl]benzene-1,3-diamine (Compound 14)

Step 1. Synthesis of tert-butyl4-[4-[3-(dimethylamino)anilino]-6-phenyl-pyrimidin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate(Intermediate C.7)

Titled compound was obtained using intermediate B.3 (120 mg, 0.37 mmol)and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate(129.5 mg, 0.41 mmol) following the general procedure reaction Cpreviously described. Final normal phase purification (cyclohexane/AcOEtfrom 100/0 to 80/20) afforded title compound (155.1 mg, yield 89%).Rt=2.48 min (analysis method 2); MS (ESI) m/z 472.3 [M-H]⁺, [M-H]⁺calculated: 472.3. ¹H NMR (400 MHz, DMSO-d₆) δ 9.44 (s, 1H), 8.17-7.95(m, 2H), 7.67-7.41 (m, 3H), 7.31 (s, 1H), 7.21 (s, 1H), 7.14 (t, J=8.1Hz, 1H), 7.11 (s, 1H), 7.03-6.93 (m, 1H), 6.42 (ddd, J=8.3, 2.7, 0.8 Hz,1H), 4.11 (s, 2H), 3.56 (t, J=5.6 Hz, 2H), 2.93 (s, 6H), 2.81-2.62 (m,2H), 1.44 (s, 9H).

Step 2. Synthesis of tert-butyl4-[4-[3-(dimethylamino)anilino]-6-phenyl-pyrimidin-2-yl]piperidine-1-carboxylate(Intermediate D.7)

Titled compound was obtained using intermediate C.7 (150 mg, 0.32 mmol)following the general procedure reaction D method previously described.Final normal phase purification (cyclohexane/AcOEt from 100/0 to 80/20)afforded pure title compound (149 mg, yield 99%). Rt=2.30 min (analysismethod 2); MS (ESI) m/z: 474.4 [M-H]⁺, [M-H]⁺ calculated: 474.3. ¹H NMR(400 MHz, DMSO-d₆) δ 9.43 (s, 1H), 8.08-7.94 (m, 2H), 7.58-7.44 (m, 3H),7.40 (s, 1H), 7.11 (t, J=8.1 Hz, 1H), 7.06 (s, 1H), 6.88 (ddd, J=7.9,2.1, 0.8 Hz, 1H), 6.41 (ddd, J=8.4, 2.5, 0.8 Hz, 1H), 4.05 (d, J=13.1Hz, 2H), 1.98 (dd, J=13.6, 3.5 Hz, 2H), 2.95-2.87 (m, 9H), 1.73 (qd,J=12.5, 4.2 Hz, 2H), 1.42 (s, 9H).

Step 3. Synthesis ofN3,N3-dimethyl-N1-[6-phenyl-2-(4-piperidyl)pyrimidin-4-yl]benzene-1,3-diamine(Compound 14)

Titled compound was obtained using intermediate D.7 (80 mg, 0.22 mmol)following the general procedure reaction E previously described. Finalnormal phase purification (DCM/DCM:NH₃ 1M MeOH 4:1 from 95/5 to 60/40)afforded pure title compound (39.6 mg, yield 34%). Rt=1.97 min (analysismethod 1); MS (ESI) m/z: 374.6 [M-H]⁺, [M-H]⁺ calculated: 374.2. ¹H NMR(400 MHz, DMSO-d₆). δ 9.42 (s, 1H), 8.01 (d, J=7.0 Hz, 2H), 7.51 (d,J=7.0 Hz, 3H), 7.40 (s, 1H), 7.12 (t, J=8.1 Hz, 1H), 7.07 (s, 1H), 6.94(d, J=8.0 Hz, 1H), 6.51-6.33 (m, 1H), 3.03 (d, J=11.9 Hz, 2H), 2.93 (s,6H), 2.85-2.70 (m, 1H), 2.61 (t, J=11.9 Hz, 2H), 2.00-1.85 (m, 2H), 1.75(qd, J=12.3, 4.3 Hz, 2H).

Example 8. N-(3-methoxyphenyl)-6-phenyl-2-(4-piperidyl)pyrimidin-4-amine (Compound 15)

Step 1. Synthesis of tert-butyl4-[4-(3-methoxyanilino)-6-phenyl-pyrimidin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate(Intermediate C.8)

Titled compound was obtained using intermediate B.4 (180 mg, 0.58 mmol)and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate(202.4 mg, 0.64 mmol) following the general procedure reaction Cpreviously described. Final normal phase purification (cyclohexane/AcOEtfrom 100/0 to 85/15) afforded title compound (241.2 mg, yield 91%).Rt=2.31 min (analysis method 2); MS (ESI) m/z 459.3 [M-H]⁺, [M-H]⁺calculated: 459.2. ¹H NMR (400 MHz, DMSO-d₆) δ 9.63 (s, 1H), 8.19-8.03(m, 2H), 7.62-7.46 (m, 4H), 7.33-7.22 (m, 2H), 7.20 (s, 1H), 7.11 (s,1H), 6.67-6.54 (m, 1H), 4.13 (d, J=3.3 Hz, 2H), 3.79 (s, 3H), 3.57 (t,J=5.7 Hz, 2H), 2.71 (s, 2H), 1.44 (s, 9H).

Step 2. Synthesis of tert-butyl4-[4-(3-methoxyanilino)-6-phenyl-pyrimidin-2-yl]piperidine-1-carboxylate(Intermediate D.8)

Titled compound was obtained using intermediate C.8 (240 mg, 0.52 mmol)following the general procedure reaction D method 1 previouslydescribed. Final normal phase purification (cyclohexane/AcOEt from 100/0to 80/20) afforded pure title compound (120 mg, yield 50%). Rt=2.11 min(analysis method 2); MS (ESI) m/z: 461.4 [M-H]⁺, [M-H]⁺ calculated:461.2. ¹H NMR (400 MHz, DMSO-d₆) δ 9.61 (s, 1H), 8.07-7.94 (m, 2H), 7.63(t, J=2.2 Hz, 1H), 7.57-7.45 (m, 3H), 7.22 (t, J=8.0 Hz, 1H), 7.17 (dt,J=8.3, 1.4 Hz, 1H), 7.08 (s, 1H), 6.59 (ddd, J=8.0, 2.5, 1.1 Hz, 1H),4.12-3.96 (m, 2H), 3.77 (s, 3H), 2.93 (tt, J=11.4, 3.7 Hz, 3H),2.06-1.95 (m, 2H), 1.72 (qd, J=12.4, 4.2 Hz, 2H), 1.42 (s, 9H).

Step 3. Synthesis ofN-(3-methoxyphenyl)-6-phenyl-2-(4-piperidyl)pyrimidin-4-amine (Compound15)

Titled compound was obtained using intermediate D.8 (115 mg, 0.25 mmol)following the general procedure reaction E previously described. Finalnormal phase purification (DCM/DCM:NH₃ 1M MeOH 4:1 from 95/5 to 50/50)afforded pure title compound (80.1 mg, yield 89%). Rt=1.85 min (analysismethod 1); MS (ESI) m/z: 361.6 [M-H]⁺, [M-H]⁺ calculated: 361.2. ¹H NMR(400 MHz, DMSO-d6). δ 9.58 (s, 1H), 8.13-7.92 (m, 2H), 7.65 (t, J=2.0Hz, 1H), 7.59-7.39 (m, 3H), 7.33-7.15 (m, 2H), 7.07 (s, 1H), 6.58 (dt,J=7.2, 2.3 Hz, 1H), 3.78 (s, 3H), 3.04 (dt, J=12.2, 3.3 Hz, 2H), 2.80(tt, J=11.6, 3.8 Hz, 1H), 2.61 (td, J=12.1, 2.5 Hz, 2H), 2.03-1.85 (m,2H), 1.74 (qd, J=12.2, 4.0 Hz, 2H).

Example 9.N1,N1-dimethyl-N4-(6-phenyl-2-tetrahydropyran-4-yl-pyrimidin-4-yl)benzene-1,4-diamine(Compound 16)

Step 1.N1-[2-(3,6-dihydro-2H-pyran-4-yl)-6-phenyl-pyrimidin-4-yl]-N4,N4-dimethyl-benzene-1,4-diamine(Intermediate C.9)

Titled compound was obtained using intermediate B.1 (115 mg, 0.35 mmol)and 3,6-Dihydro-2H-pyran-4-boronic acid pinacol ester (91.1 mg, 0.42mmol) following the general procedure reaction C previously described.Final normal phase purification (cyclohexane/AcOEt from 90/10 to 70/30)afforded title compound (37.1 mg, yield 28%). Rt=1.70 min (analysismethod 2); MS (ESI) m/z 373.5 [M-H]⁺, [M-H]⁺ calculated: 373.2. ¹H NMR(400 MHz, DMSO-d₆) δ 9.29 (s, 1H), 8.03 (dd, J=7.7, 1.9 Hz, 2H),7.58-7.43 (m, 5H), 7.25-7.12 (m, 1H), 6.96 (s, 1H), 6.81-6.71 (m, 2H),4.32 (q, J=2.7 Hz, 2H), 3.83 (t, J=5.4 Hz, 2H), 2.87 (s, 6H), 2.71-2.58(m, 2H).

Step 2.N4,N4-dimethyl-N1-(6-phenyl-2-tetrahydropyran-4-yl-pyrimidin-4-yl)benzene-1,4-diamine(Compound 16)

Titled compound was obtained using intermediate C.9 (35 mg, 0.09 mmol)following the general procedure reaction D method previously described.Final normal phase purification (cyclohexane/AcOEt from 95/5 to 75/25)afforded pure title compound (27 mg, yield 77%). Rt=1.48 min (analysismethod 2); MS (ESI) m/z: 375.5 [M-H]⁺, [M-H]⁺ calculated: 375.2. ¹H NMR(400 MHz, DMSO-d₆) δ 9.27 (s, 1H), 8.05-7.91 (m, 2H), 7.63-7.40 (m, 4H),6.93 (s, 1H), 6.83-6.68 (m, 2H), 3.96 (dt, J=11.4, 2.6 Hz, 2H), 3.48(td, J=11.1, 3.5 Hz, 2H), 2.93 (dq, J=10.7, 5.8, 5.3 Hz, 1H), 2.88 (s,5H), 1.96-1.77 (m, 4H).

Example 10.N-(4-methoxyphenyl)-6-phenyl-2-tetrahydropyran-4-yl-pyrimidin-4-amine(Compound 17)

Step 1.2-(3,6-dihydro-2H-pyran-4-yl)-N-(4-methoxyphenyl)-6-phenyl-pyrimidin-4-amine(Intermediate C.10)

Titled compound was obtained using intermediate B.2 (90 mg, 0.29 mmol)and 3,6-Dihydro-2H-pyran-4-boronic acid pinacol ester (74.3 mg, 0.35mmol) following the general procedure C previously described. Finalnormal phase purification (cyclohexane/TBME from 100/0 to 80/20)afforded title compound (44.2 mg, yield 43%). Rt=1.54 min (analysismethod 2); MS (ESI) m/z 360.5 [M-H]⁺, [M-H]⁺ calculated: 360.2. ¹H NMR(400 MHz, DMSO-d₆) δ 9.45 (s, 1H), 8.12-8.01 (m, 2H), 7.65 (d, J=8.9 Hz,2H), 7.57-7.45 (m, 5H), 7.01 (s, 1H), 6.98-6.92 (m, 1H), 4.33 (d, J=2.9Hz, 2H), 3.76-3.72 (m, 5H), 2.71-2.61 (m, 2H).

Step 2.N-(4-methoxyphenyl)-6-phenyl-2-tetrahydropyran-4-yl-pyrimidin-4-amine(Compound 17)

Titled compound was obtained using intermediate C.10 (42 mg, 0.12 mmol)following the general procedure reaction D method 2 previouslydescribed. Final normal phase purification (cyclohexane/TBME from 90/10to 70/30) afforded pure title compound (16 mg, yield 38%). Rt=1.31 min(analysis method 2); MS (ESI) m/z: 362.5 [M-H]⁺, [M-H]⁺ calculated:362.2. ¹H NMR (400 MHz, DMSO-d₆) δ 9.43 (s, 1H), 8.11-7.88 (m, 2H), 7.63(d, J=8.5 Hz, 2H), 7.55-7.45 (m, 3H), 6.98 (s, 1H), 6.96-6.90 (m, 2H),3.96 (ddd, J=11.3, 4.2, 2.3 Hz, 2H), 3.75 (s, 3H), 3.47 (td, J=11.3, 3.0Hz, 2H), 3.03-2.88 (m, 1H), 1.98-1.77 (m, 4H).

Cell Viability Assay

Cells were seeded at 10,000 cells/well in 96-well plates and incubatedfor 24 h at 37° C. with 5% CO₂. After an overnight incubation, cellswere treated with inhibitor (1.25-50 μM) alone or with Cisplatin at 20μM for 24 hours. The cell viability was determined using the CellTiter-Glo luminescent cell viability assay kit (Promega, Madison, Wis.),according to the manufacturer's instructions. Luminescence was measuredusing a DTX 800 microplate reader (Coulter). The half-maximal inhibitoryconcentration (IC50) values were calculated using the GraphPad Prismsoftware. The assay was done by conducting 3 independent experiments.

The results are illustrated in Table 1

TABLE 1 Compound number Structure Potency  1 (ARN12405)

IC₅₀ (alone) 16.4 μM IC₅₀ (CisPt) 12.8 μM  2

IC₅₀ (alone) 14.9 μM IC₅₀ (CisPt) 11.5 μM  3

IC₅₀ (alone) 29.0 μM IC₅₀ (CisPt) 38.2 μM  4

IC₅₀ (alone) 10.2 μM IC₅₀ (CisPt) 7.0 μM  5

IC₅₀ (alone) 38.3 μM IC₅₀ (CisPt) 42.3 μM  6

IC₅₀ (alone) 19.7 μM IC₅₀ (CisPt) 17.0 μM  7

IC₅₀ (alone) 40.1 μM IC₅₀ (CisPt) 32.0 μM  8

IC₅₀ (alone) 45.0 μM IC₅₀ (CisPt) 31.4 μM  9

IC₅₀ (alone) >50 μM IC₅₀ (CisPt) >50 μM 10

IC₅₀ (alone) 45.02 μM IC₅₀ (CisPt) 31.4 μM 11

IC₅₀ (alone) 24.2 μM IC₅₀ (CisPt) 27.8 μM 12

IC₅₀ (alone) 27.0 μM IC₅₀ (CisPt) 86.3 μM 13

IC₅₀ (alone) 32.5 μM IC₅₀ (CisPt) 36.7 μM 14

IC₅₀ (alone) 24.8 μM IC₅₀ (CisPt) 17.2 μM 15

IC₅₀ (alone) 38.2 μM IC₅₀ (CisPt) 22.2 μM 16

IC₅₀ (alone) >50 μM IC₅₀ (CisPt) >50 μM 17

IC₅₀ (alone) >50 μM IC₅₀ (CisPt) >50 μM

Flow cytometric analyses for apoptosis Approximately 1×10⁶ melanomacells treated with inhibitors for 24 hours and were then trypsinized andwashed with PBS, the single-cell suspensions were incubated with AlexaFluor-Annexin V and propidium iodide (PI) (V13245; Invitrogen) per themanufacturer's protocol and were subjected to flow cytometric analysis.In all cases, cell debris was gated out on the basis of forward scatterand side scatter analysis. Data was analyzed using FlowJo (Ashland,Oreg.). Results are illustrated in FIG. 1, wherein WM3248 melanoma cellswere treated with the indicated doses of compound 1 (ARN12405) andapoptosis was measured by flow cytometry using Annexin V and PI.

Cdc42 Activity Assays

A Cdc42 activation assay was performed according the manufacturer'sprotocol (Cell Biolabs, San Diego, Calif.). Briefly, cells treated withthe inhibitor were lysed and either loaded with GDP or GTPyS. Agarosebeads conjugated with the PAK1 PBD domain pulled down Cdc42, Rac1, orRhoJ only when GTP-bound. Lysates were then immunoblotted with indicatedAbs. Results are illustrated in FIG. 2. In particular, a Cdc42activation assay was used to determine whether the inhibitor blocked theability of RhoJ to interact with PAK coupled beads. Briefly, cells weretreated with compound 1 (ARN12405) and cell lysates were prepared andincubated with PAK coupled beads. Immunoprecipitated proteins weresubjected to SDS PAGE and immunoblotted with a (A) RhoJ antibody, (B)Cdc42 antibody, (C) Rac1 antibody, (D) Cells were treated with one of apanel of RhoJ interaction inhibitors at a concentration of 10 μm or 50μm (see FIG. 2, panels A-D). Lysates were prepared, incubated with PAKcoupled beads, and immunoprecipitated proteins were immunoblotted with aRhoJ antibody.

The invention claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: A is a6-membered aromatic ring or a 6-membered heteroaromatic ring, whereinthe 6-membered heteroaromatic ring contains 1 or 2 nitrogen atoms, andfurther wherein the 6-membered aromatic ring or the 6-memberedheteroaromatic ring is optionally substituted with 1 substituentselected from the group consisting of halogen, C₁₋₆ alkyl, C₁₋₆alkyl(halo), C₁₋₆ alkyl(alkoxy), NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂,and OH; A′ is a 6-membered aromatic ring or a 6-membered heteroaromaticring, wherein the 6-membered heteroaromatic ring contains 1 or 2nitrogen atoms, and further wherein the 6-membered aromatic ring or the6-membered heteroaromatic ring is optionally substituted with 1substituent selected from the group consisting of halogen, C₁₋₆ alkyl,C₁₋₆ alkyl(halo), C₁₋₆ alkyl(alkoxy), NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆alkyl)₂, and OH; X₁ is —CH₂—, —NR₂—, or —O—; X₂ is —CH₂—, —NR₂—, or —O—;R₁ is H or C₁₋₆ alkyl; R₂ is H, C₁₋₆ alkyl, C₁₋₆ alkyl(alkoxy), C(O)C₁₋₆alkyl, or C(O)C₁₋₆ alkyl(alkoxy); and Y is CH; with the provisos that:(1) X₁ and X₂ are not simultaneously —NR₂—; (2) X₁ and X₂ are notsimultaneously —NR₂— and —O—; and (3) X₁ and X₂ are not simultaneously—O—.
 2. The compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, wherein A is an unsubstituted 6-memberedaromatic ring or a 6-membered heteroaromatic ring, wherein the6-membered heteroaromatic ring contains 1 nitrogen atom.
 3. The compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof,wherein A′ is a 6-membered aromatic ring, wherein the 6-memberedaromatic ring is substituted in the meta position or the para positionwith 1 N(CH₃)₂ substituent.
 4. The compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein: A is a 6-memberedaromatic ring or a 6-membered heteroaromatic ring, wherein the6-membered heteroaromatic ring contains 1 nitrogen atom, and furtherwherein the 6-membered aromatic ring or the 6-membered heteroaromaticring is optionally substituted with 1 substituent selected from thegroup consisting of halogen, NH₂, NH(C₁₋₆ alkyl), and N(C₁₋₆ alkyl)₂; A′is a 6-membered aromatic ring or a 6-membered heteroaromatic ring,wherein the 6-membered heteroaromatic ring contains 1 nitrogen atom, andfurther wherein the 6-membered aromatic ring or the 6-memberedheteroaromatic ring is optionally substituted with 1 substituentselected from the group consisting of halogen, NH₂, NH(C₁₋₆ alkyl), andN(C₁₋₆ alkyl)₂; R₁ is H; and R₂ is H.
 5. The compound according to claim1, or a pharmaceutically acceptable salt thereof, wherein: A is a6-membered aromatic ring or a 6-membered heteroaromatic ring, whereinthe 6-membered heteroaromatic ring contains 1 nitrogen atom in position2 or position 3, and further wherein the 6-membered aromatic ring isoptionally substituted with 1 halogen substituent; A′ is a 6-memberedaromatic ring, wherein the 6-membered aromatic ring is optionallysubstituted in the meta position or the para position with 1 substituentselected from the group consisting of halogen and N(C₁₋₆ alkyl)₂; X₁ is—CH₂—, —NR₂—, or —O—; X₂ is —CH₂— or —NR₂—; R₁ is H; and R₂ is H.
 6. Thecompound according to claim 1, wherein the compound is selected from thegroup consisting of:

or a pharmaceutically acceptable salt thereof.
 7. A medicamentcomprising the compound according to claim 1, or a pharmaceuticallyacceptable salt thereof.
 8. The medicament according to claim 7, whereinthe medicament further comprises at least one pharmaceuticallyacceptable excipient.
 9. A pharmaceutical composition comprising atleast one pharmaceutically acceptable excipient and the compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof. 10.The pharmaceutical composition according to claim 9, wherein thepharmaceutical composition further comprises a chemotherapeutic agentselected from the group consisting of carboplatin, cisplatin,dacarbazine, nedaplatin, oxaliplatin, satraplatin, temozolamide, andtriplatin tetranitrate.
 11. The pharmaceutical composition according toclaim 10, wherein the pharmaceutical composition is administeredseparately, simultaneously, or sequentially.
 12. A method for inhibitingRhoJ activity or cell division control protein 42 homolog-guanosinetriphosphate hydrolyzing protein activity in a subject, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of the compound according to claim 1, or a pharmaceuticallyacceptable salt thereof.
 13. The method according to claim 12, whereinthe subject has a disease or disorder selected from the group consistingof a metastatic neoplastic disease, a primary neoplastic disease, and apre-malignant condition.
 14. The method according to claim 13, whereinthe metastatic neoplastic disease, the primary neoplastic disease, orthe pre-malignant condition is selected from the group consisting of abenign tumor, a cancer, a cancer metastasis, a cardiomyopathy, adysplasia, a hyperplasia, a hyperproliferative disorder, a metaplasia,and a retinal disorder.
 15. The method according to claim 14, whereinthe cancer is melanoma.
 16. A method for inhibiting RhoJ activity orcell division control protein 42 homolog-guanosine triphosphatehydrolyzing protein activity in a subject, comprising administering tothe subject in need thereof a therapeutically effective amount of thepharmaceutical composition according to claim
 9. 17. The methodaccording to claim 16, wherein the subject has a disease or disorderselected from the group consisting of a metastatic neoplastic disease, aprimary neoplastic disease, and a pre-malignant condition.
 18. Themethod according to claim 17, wherein the metastatic neoplastic disease,the primary neoplastic disease, or the pre-malignant condition isselected from the group consisting of a benign tumor, a cancer, a cancermetastasis, a cardiomyopathy, a dysplasia, a hyperplasia, ahyperproliferative disorder, a metaplasia, and a retinal disorder. 19.The method according to claim 18, wherein the cancer is melanoma.
 20. Acompound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.